ArticleChemMedChem2020
Structure-Based Design of FXIIIa-Blockers: Addressing a Transient Hydrophobic Pocket in the Active Site of FXIIIa.
Article in ChemMedChem, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 4 citations in OpenAlex.
- Discovery of Heparin Mimetic, Potent, and Selective Inhibitors of Human Clotting Factor XIIIa.ACS omega · 2024Article
- Autoantibody binding and unique enzyme-substrate intermediate conformation of human transglutaminase 3.Nature communications · 2023Article
- Peptidic Inhibitors and a Fluorescent Probe for the Selective Inhibition and Labelling of Factor XIIIa Transglutaminase.Molecules (Basel, Switzerland) · 2023Article
- Structure-Based Design of FXIIIa-Blockers: Addressing a Transient Hydrophobic Pocket in the Active Site of FXIIIa.ChemMedChem · 2020Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Blood coagulation factor XIII (FXIII, F13) is considered to be a promising target for anticoagulants with reduced bleeding risk because of its unique position in the coagulation cascade downstream of thrombin. However, until now, no potent drug addressing FXIII has been available, indeed no compound has even entered clinical trials yet. In 2013, we published the co-crystal structure of FXIII in the active state (FXIIIa°), thereby providing a detailed map of the active site for the rational design of potent FXIIIa blockers. Here we report, for the first time, a structure-based approach to improving the affinity of FXIIIa inhibitors. FXIII was crystallized in complex with a methyl thiazole moiety to address a novel transient hydrophobic pocket close to the catalytic center. By subsequent structure-based design to rationalize the introduction of an ethyl ester, the potency of the inhibitor was improved significantly compared to that of the parent lead compound. The occupancy of the hydrophobic pocket described here might turn out to be a key step in the development of a potent reversible and orally available FXIIIa blocker.
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